(a) Field of Invention
This invention relates to sulfur-free penicillin derivatives and more particularly to derivatives of 2-azetidinyl-3-methyl-2-butenoates having two different functions at the 3-methyl and at the terminal methyl groups of the 2-butenoate chain and to a process for preparing said derivatives. The derivatives of the present invention are particularly useful as intermediates in the synthesis of 1-oxacephems having substitutents other than methyl and hydroxyl attached to carbon-3 of the six membered ring. 1-Oxacephems are cephalosporin analogs in which the sulfur atom of the six membered ring has been replaced by oxygen. The 1-oxacephems have been found to possess anti-bacterial activity in any of their free acid, salt or active ester forms.
(b) Prior Art
Numerous routes for the synthesis of the 1-oxacephem ring system have been described in the literature and these are believed to be the most relevant prior art relating to the present invention. In addition, at least six different methods exist for the replacement of R=H of structures 1, A, B, C, D and the corresponding hydrogen of penicillins, cephalosporins and oxacephems by R=OCH.sub.3 (Topics in Antibiotic Chemistry, Vol. 4, Edited by P. Sammes, pp 196-210).
The first publications on 1-oxacephems appeared simultaneously in the Canadian Journal of Chemistry, Volume 52, page 3996 (1974) by S. Wolfe et al, and in the Journal of the American Chemical Society, Volume 96, page 7582 (1974) by B. G. Christensen et al, and illustrate the two main lines followed subsequently by other workers.
In the approach employed by S. Wolfe et al, the starting material was penicillin, which was converted to a 2-azetidinyl-3-methyl-2-butenoate. ##STR2## The isoprenoid skeleton attached to the nitrogen atom of the azetidinyl moiety was retained during the remainder of the sequence, which was therefore directed towards a Z-2-azetidinyl-4-hydroxy-3-methyl-2-butenoate, e.g., 1, R.sub.2 =H, which was finally cyclized to form the 1-oxacephem (see also Canadian Pat. No. 1,052,787 issued Apr. 17, 1979 to Wolfe). Variations of this approach have been described by C. U. Kim and D. N. McGregor, Tetrahedron Letters, page 409 (1978), Y. Hamashima et al, Tetrahedron Letters, page 4943 (1979), J. E. Baldwin et al, Tetrahdedron, Volume 36, page 1627 (1980), and J. L. Pfeil et al, Journal of Organic Chemistry, Volume 46, page 827 (1981). A review of several approaches, including this one, to the antibacterial agent "Moxalactam".RTM. is given by W. Nagata, Philosophical Transactions of the Royal Society, Part B, Volume 289, page 225 (1980).
In the approach used by B. G. Christensen et al, a phosphorus-containing compound such as B or C was subjected to an intramolecular Wittig cyclization to form the six-membered ring. Compounds such as B or C (below) may be prepared by total synthesis, as in the work of B. G. Christensen et al, or by partial synthesis from a penicillin or cephalosporin precursor. In the latter case, as described by R. B. Woodward et al, Nouveau Journal de Chimie, Volume 1, page 85 (1977), and first disclosed by K. Heusler in Cephalosporins and Penicillins, Chemistry and Biology, Edited by E. H. Flynn, Academic Press, New York, 1972, page 274, the isoprenoid moiety is detached from the azetidinyl nitrogen atom of a compound such as A, and the required phosphorane or phosphonate is constructed by successive reactions with a glyoxylate ester, thionyl chloride, and a phosphorous compound. Examples of the latter approach have been reviewed, inter alia, by E. T. Gunda and J. Cs. Jaszberenyi, Progress in Medicinal Chemistry, Edited by G. P. Ellis and G. B. West, Elsevier/North Holland Biomedical Press, Volume 12, Chapter 8 and Volume 14, Chapter 4, 1975 and 1977; also in Topics in Antibiotic Chemistry, Edited by P. G. Sammes, Volume 4, Ellis Horwood Limited, 1980, Chapters 2 and 3. According to Nagata (op cit), this multi-step approach necessitates the repetitive steps of removing and supplying several carbon atoms, and results in a very low overall yield of the final product. ##STR3##
In the work of Yamashima et al (op cit) and M. M. Campbell et al, Tetrahedron Letters, page 1257 (1979), compounds of type D, which contain a 2-azetidinyl-3- and 4-functionalized-2-butenoate (R.sup.1 =OCHO, R.sup.2 =OCHO, OCOCH.sub.3) were found to be unsuitable for the preparation of 1-oxacephem compounds, because of problems associated with the removal of the R.sup.1 protecting group in the presence of an oxazoline ring.
Although some of the processes disclosed in the Prior Art use functionalized derivatives of 2-azetidinyl-3-methyl-2-butenoates as intermediates, none of those processes has succeeded so far in preparing such intermediates having two different functions at the 3-methyl and at the terminal methyl groups of the 2-butenoate chain. Such intermediates would be particularly valuable for the preparation of 1-oxacephem antibiotics having a methylthioheterocyclyl substitutent in position 3 of the 1-oxacephem ring system, because they would enable the chemist to introduce such a substituent in a particularly facile manner.
(c) Objects of the Invention
An object of the present invention is to provide intermediates of the general formula: ##STR4## in which:
R is hydrogen or methoxy,
R.sub.1 is a hydroxyl group,
R.sub.2 is chlorine, bromine, OCOCH.sub.3 or SHET,
R.sub.3 is hydrogen or a group selected from loweralkyl, benzyl, benzhydryl, loweralkoxyloweralkyl, loweralkoxybenzyl, phenacyl, trimethylsilyl, 2,2,2-trichloroethyl or pivaloyl,
R.sub.4 is hydrogen or a cleavable acyl group, or R.sub.4 NH represents phthalimido, and
HET is a five membered aromatic heterocycle containing 1-4 heteroatoms and optionally substituted with loweralkyl di-lower alkylamino, mono-lower alkylamino, formylamino, alkanoylamino of 2 to 5 carbons, halogen, amino, cycloalkyl containing 3-7 carbon atoms or lower alkoxy.
Another object of the present invention is to provide a simple and efficient process for the production of the intermediate Compound 1 from a 2-azetidinyl-3-methyl-2-butenoate.
Yet another object of the present invention is to provide a process for the cyclization of the intermediate compounds 1 to 1-oxacephems of the general formula ##STR5## where R.sub.3 is as heretobefore described, R.sub.4 is hydrogen, and R.sub.2 is a substituted methyl not a methyl group, which compounds are readily convertible to a range of compounds of the general formula ##STR6## where R.sub.2 and R.sub.4 are as hereinbefore described, and the methoxyl group at C(7) has been introduced by one of the procedures noted in the Prior Art.
These intermediates are readily convertible to known oxacephem anti-bacterial agents such as Moxalactam.RTM. by known methods. For example the compound of formula 1 in which R is hydrogen, R.sub.1 is hydroxy, R.sub.2 is SHET in which HET is 1-methyl-1H-tetrazol-5-yl, R.sub.3 is a cleavable carboxy-protecting group, e.g. diphenylmethyl, and R.sub.4 is a cleavable amino-protecting group, e.g. trichloroethoxycarbonyl, may be treated with t-butyldiphenylchlorosilane to obtain the corresponding t-butyldiphenylsilyl derivative which is then cyclized by treatment with fluoride ions to yield the corresponding 1-oxacephem derivative of formula I ##STR7## in which R is hydrogen, R.sub.3 and R.sub.4 are as defined above, W is sulfur, and Z is 1-methyl-1H-tetrazol-5-yl; treatment of said last-named compound with activated zinc yields the corresponding free 7.beta.-amino compound which is identical with compound (II) described in Drugs of the Future, Vol. IV, No. 9, 667-671 (1979) which also shows the conversion of the latter compound to Moxalactam.RTM.. Alternatively, the compound of formula I in which R, R.sub.3, R.sub.4, W and Z are as defined above may be treated with t-butylhypochlorite and lithium methoxide in the manner described by Nagata (op.cit) to obtain the corresponding compound of formula I in which R is methoxy, R.sub.3, R.sub.4, W and Z are as defined above, and which is identical with compound 32 of Chart 6 of the above reference; the conversion of the latter compound to Moxalactam.RTM. is then described in Chart 7 of said reference. Other pathways will be apparent to those skilled in the art.
The term "acyl" as used herein includes 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl and in general alkoxycarbonyl or aryloxycarbonyl, alkyl or arylcarbamoyl and the like, since such compounds do not undergo intramolecular displacement of chlorine by acyl under the conditions of cyclization to the oxacephem ring system.
Carboxy or protected carboxy groups conventional in the chemistry of penicillins and cephalosporins, usually contain up to 20 carbon atoms and are preferably selected from loweralkyl, benzyl, benzhydryl, loweralkoxyloweralkyl, loweralkoxybenzyl, phenacyl, trimethylsilyl, 2,2,2-trichloroethyl or pivaloyl. The protective groups can be the same or different for each carboxyl in the molecule. The structures of the carboxy protecting groups can vary widely without changing the import of this invention. Usually the protective groups are removed to give free carboxy or salts, at any stage of synthesis. Therefore, the structures of the carboxy-protective groups can vary widely without changing the gist of this invention. In other words, their structures have no specific significance other than protection, deprotection, ##STR8## where R.sub.2 and R.sub.4 are as hereinbefore described, and the methoxyl group at C(7) has been introduced by one of the procedures noted in the Prior Art.
These intermediates are readily convertible to known oxacephem anti-bacterial agents such as Moxalactam.RTM. by known methods.
The term "acyl" as used herein includes 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl and in general alkoxycarbonyl or aryloxycarbonyl, alkyl or arylcarbamoyl and the like, since such compounds do not undergo intramolecular displacement of chlorine by acyl under the conditions of cyclization to the oxacephem ring system.
Carboxy or protected carboxy groups conventional in the chemistry of penicillins and cephalosporins, usually contain up to 20 carbon atoms and are preferably selected from loweralkyl, benzyl, benzhydryl, loweralkoxyloweralkyl, loweralkoxybenzyl, phenacyl, trimethylsilyl, 2,2,2-trichloroethyl or pivaloyloxy. The protective groups can be the same or different for each carboxyl in the molecule. The structures of the carboxy protecting groups can vary widely without changing the import of this invention. Usually the protective groups are removed to give free carboxy or salts, at any stage of synthesis. Therefore, the structures of the carboxyprotective groups can vary widely without changing the gist of this invention. In other words, their structures have no specific significance other than protection, deprotection, and, when included, salt formation.
Specific examples of said protective groups are esters (including optionally substituted 1-5C esters, e.g. methyl, ethyl, isopropyl, n-butyl, t-butyl, pentyl, cyclopropylmethyl, monohydroxy-t-butyl, 2,2,2-trichloroethyl, chloromethyl, cyanomethyl, methanosulfonylethyl, acetylmethyl, acetoxymethyl, propionyloxymethyl, benzoyloxymethyl, methoxymethyl, phenoxymethyl, methylthiomethyl, phenylthiomethyl, tetrahydropyranyl, phthalimidomethyl, .alpha.,.alpha.-dimethylpropargyl, ethoxycarbonyloxyethyl, methoxycarbonyloxypropyl, and allyl esters; aralkyl esters e.g. benzyl, phenethyl, tolylmethyl, dimethylbenzyl, nitrobenzyl, halobenzyl, methoxybenzyl, phthalidyl, p-hydroxy-di-t-butylbenzyl, diphenylmethyl, trityl, phenacyl, chlorophenacyl, bromophenacyl, nitrophenacyl, and methylphenacyl esters; and other easily removable aliphatic esters; metal esters, e.g. trimethylsilyl, dimethylmethoxysilyl, trimethylstannyl esters; and aromatic esters, e.g. phenyl, naphthyl, tolyl, dimethylphenyl, nitrophenyl, methanosulfonylphenyl, chlorophenyl, pentachlorophenyl, indenyl, and pyridyl esters); or pharmaceutically acceptable salts (including alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. magnesium, calcium and acyloxycalcium salts; and salts with organic bases, e.g. procaine, triethylamine and dicyclohexylamine). Each carboxy in the molecule can be free or protected by the same or different groups.
The heterocyclic ring HET in SHET is a 5 membered ring and has 1 to 4, preferably 1-3 heteroatoms which are the same or different and contain oxygen, sulphur or nitrogen. An unsaturated heterocyclic ring containing 2 double bonds is preferred. The heterocyclic ring can have one or several, preferably 1 or 2, substitutions therein. The substituent can be selected from: halogen, such as fluorine, chlorine, bromine and iodine and preferably chlorine and bromine, amino, lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in cycloalkyl), lower alkyloxy, trifluoromethyl, phenyl, benzyl, and acylamino with preferably 2-5 and even more preferred 2 or 3 carbon atoms. Examples of preferred HET include furyl, thienyl, ##STR9##
Illustrative of the compounds 1 of the present invention ##STR10## which is methyl 2-(2'-oxo-3'S-trichloroethoxycarbonylamino-4'-chloro) azetidinyl-3-bromomethyl-4-formyloxy-trans-2-butenoate.
Other examples include:
______________________________________ R.sub.3 R.sub.2 R.sub.1 R.sub.4 ______________________________________ CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OCHO CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OCHO CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OCHO CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 Br OH CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OH CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OH CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OH CCl.sub.3 CH.sub.2 OCO CH.sub.2 CCl.sub.3 or CH.sub.3 Br OH PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OH PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OH PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OH PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 Br OCHO PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OCHO PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OCHO PhOCO CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OCHO PhOCO ______________________________________ or R.sub.3 R.sub.2 R.sub.1 R.sub.4 NH ______________________________________ CH.sub.2 CCl.sub.3 or CH.sub.3 Br OCHO Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OCHO Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OCHO Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OCHO Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 Br OH Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 Cl OH Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 OAc OH Phthalimido CH.sub.2 CCl.sub.3 or CH.sub.3 S Het OH Phthalimido ______________________________________